Inhibitors of serine protease activity, methods and compositions for treatment of viral infections

Abstract

A novel method of treating and preventing viral infection is provided. In particular a method of blocking viral infection facilitated by a serine proteolytic (SP) activity is disclosed, which consists of administering to a subject suffering or about to suffer from viral infection a therapeutically effective amount of a compound having a serine protease inhibitory or serpin activity. Among compounds are α1-antitrypsin (AAT), peptide derivatives from the carboxyterminal end of AAT, and man-made, synthetic compounds mimicking the action of such compounds. The preferred viral infections include retroviral infection such as human immunodeficiency virus (HIV) infection.

Description

[0002]This application claims priority to U.S. Provisional Application No. 60 / 123,167 filed Mar. 5, 1999 and U.S. Provisional Application No. 60 / 137,795 filed Jun. 3, 1999 both of which are hereby incorporated by reference.FIELD OF THE INVENTION[0003]In general, the present invention relates to enzyme inhibitors and their respective ligands. More particularly, the present invention relates to substances exhibiting inhibitory activity toward retroviral replication and spread, which are facilitated or mediated by serine protease activity.BACKGROUND AND SUMMARY OF THE INVENTION[0004]Serine proteases serve an important role in human physiology by mediating the activation of vital functions. In addition to their normal physiological function, serine proteases have been implicated in a number of pathological conditions in humans. Serine proteases are characterized by a catalytic triad consisting of aspartic acid, histidine and serine (Asp-His-Ser) at the active site.[0005]The naturally oc...

AI Technical Summary

Benefits of technology

[0009]AAT easily diffuses into tissue spaces and forms a 1:1 complex with a target protease, principally neutrophil elastase. Human neutrophil elastase (NE) is a proteolytic enzyme secreted by polymorphonuclear leukocytes in response to a variety of inflammatory stimuli. The degradative capacity of NE, under normal circumstances, is modulated by relatively high plasma concentrations of α1-antitrypsin (AAT). However, stimulated neutrophils produce a burst of active oxygen metabolites, some of which (hypochlorous acid for example) are capable of oxidizing a critical methionine residue in AAT. Oxidized AAT has been shown to have a limited potency as a NE inhibitor and it has been proposed that alteration of this protease / antiprotease balance permit NE to perform its degradative functions in a non-localized and uncontrolled fashion.

[0037]In the course of the AIDS progression, many measurable clinical parameters including AAT progressively increase (Cordiali Fei et al., “Behavior of several ‘progression markers’ during the HIV-Ab seroconversion period. Comparison with later stages”, J Biol Regul Homeost Agents, 6(2);57-64) (1992). AAT was positive in 40% of HIV-positive patients with cryptosporidial infections and none of 12 HIV-positive patients with non-cryptosporidial diarrhea (Lima et al., “Mucosal injury and disruption of intestinal barrier function in HIV-1-infected individuals with and without diarrhea and cryptosporidiosis in northeast Brazil”, Am J Gastroenterol, 92(10):1861-6) (1997). Scrum concentrations of a tumor-associated trypsin inhibitor (TATI) were very high in some HIV positive subjects and especially in AIDS patients (Banfi et al., “Tumor-associated trypsin inhibitor in induced and acquired immunodeficiency. Studies on transplanted and HIV-infected patients”, Scand J Clin Lab Invest Suppl, 207:55-8 (1991)). The incidence of abnormal AAT phenotypes was 16.3% in the homosexual group which was significantly different (p less than 0.03) than the 8.7% in the heterosexual group. There was no difference in the phenotype distribution between homosexuals who were anti-HIV antibody reactive and those who were non-reactive (Deam et al., “Alpha 1-antitrypsin phenotypes in homosexual men”, Pathology, 21(2):91-2) (1989). Faecal alpha1 antitrypsin concentration were reflective of abnormal pancreatic function of paediatric HIV infection (Carroccio et al., “Pancreatic dysfunction and its association with fat malabsorption in HIV infected children”, Gut, 43(4):55863) (1998). Patients with HIV-1 infection are known to acquire an obstructive pulmonary disease with clinical similarity to emphysema. AAT levels measured in these patients were in the lower normal range. Despite observing these clinical findings in 42% of consecutive HIV-1-infected patients in the clinic, no evidence of current of previous opportunistic infection was detected. Bronchoalveolar lavage fluid obtained in a subset of these patients contained TNF and free radicals, indicating inflammation. It is possible that HIV-1 associated free radical production inactivated pulmonary AAT and facilitated the development of the cryptogenic emphysema-like condition.

[0043]It is an object of the present invention to provide clinically acceptable serine protease inhibitors with recognized utility and exhibiting relatively high activity at relatively low concentrations.

Problems solved by technology

In some instances the degradative action of serine proteases results in serious pathological conditions or disease states.

Disruption of the elastase / AAT balance leads to increased elastin degradation and, hence, to elastic tissue destruction.

While some earlier reports identifying various proteases such as Kunitz type tryptase TL2 seem to have been confirmed, other enzymes as facilitators of HIV infection failed to pass rigorous scientific scrutiny.

Yet, despite all these efforts not a single compound has been considered as clinically acceptable.

Also, high levels of serum trypsin and elastase are present in an elevated percentage of patients with AIDS, suggesting that the pancreas is frequently damaged in this disease.

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